EP1425019B1 - Pharmazeutische zusammensetzung enthaltend ein androgen - Google Patents
Pharmazeutische zusammensetzung enthaltend ein androgen Download PDFInfo
- Publication number
- EP1425019B1 EP1425019B1 EP03726373A EP03726373A EP1425019B1 EP 1425019 B1 EP1425019 B1 EP 1425019B1 EP 03726373 A EP03726373 A EP 03726373A EP 03726373 A EP03726373 A EP 03726373A EP 1425019 B1 EP1425019 B1 EP 1425019B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- testosterone
- androgen
- weight
- composition
- pharmaceutical composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000003098 androgen Substances 0.000 title claims description 96
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 25
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims description 266
- 239000000203 mixture Substances 0.000 claims description 223
- 229960003604 testosterone Drugs 0.000 claims description 130
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 89
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 claims description 74
- 229960003473 androstanolone Drugs 0.000 claims description 67
- 210000002966 serum Anatomy 0.000 claims description 58
- 239000002562 thickening agent Substances 0.000 claims description 53
- 239000003623 enhancer Substances 0.000 claims description 49
- FKUPPRZPSYCDRS-UHFFFAOYSA-N Cyclopentadecanolide Chemical group O=C1CCCCCCCCCCCCCCO1 FKUPPRZPSYCDRS-UHFFFAOYSA-N 0.000 claims description 41
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 31
- 239000012528 membrane Substances 0.000 claims description 22
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 230000003472 neutralizing effect Effects 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 14
- 206010022998 Irritability Diseases 0.000 claims description 14
- 238000002425 crystallisation Methods 0.000 claims description 14
- 230000008025 crystallization Effects 0.000 claims description 14
- 229920002125 Sokalan® Polymers 0.000 claims description 13
- 229920001577 copolymer Polymers 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 13
- 238000009472 formulation Methods 0.000 claims description 13
- 239000003112 inhibitor Substances 0.000 claims description 13
- 210000004369 blood Anatomy 0.000 claims description 12
- 239000008280 blood Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- 229940096529 carboxypolymethylene Drugs 0.000 claims description 10
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 229940042129 topical gel Drugs 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 5
- 239000002243 precursor Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 3
- 150000003515 testosterones Chemical class 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000000227 bioadhesive Substances 0.000 claims 1
- 229960001631 carbomer Drugs 0.000 claims 1
- 239000000039 congener Substances 0.000 claims 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 45
- 239000000499 gel Substances 0.000 description 33
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 25
- 229940068196 placebo Drugs 0.000 description 25
- 239000000902 placebo Substances 0.000 description 25
- 210000003491 skin Anatomy 0.000 description 25
- 210000004379 membrane Anatomy 0.000 description 20
- 201000003585 eunuchism Diseases 0.000 description 14
- 208000037106 male hypogonadism Diseases 0.000 description 14
- 239000004615 ingredient Substances 0.000 description 13
- 238000011282 treatment Methods 0.000 description 13
- 235000011187 glycerol Nutrition 0.000 description 12
- -1 dioxane compound Chemical class 0.000 description 11
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 10
- 239000003974 emollient agent Substances 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 125000004122 cyclic group Chemical group 0.000 description 8
- 239000003755 preservative agent Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000007792 addition Methods 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 230000003247 decreasing effect Effects 0.000 description 7
- 239000002202 Polyethylene glycol Substances 0.000 description 6
- 206010040880 Skin irritation Diseases 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000003149 assay kit Methods 0.000 description 6
- OSOIQJGOYGSIMF-UHFFFAOYSA-N cyclopentadecanone Chemical compound O=C1CCCCCCCCCCCCCC1 OSOIQJGOYGSIMF-UHFFFAOYSA-N 0.000 description 6
- 230000007423 decrease Effects 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 231100000475 skin irritation Toxicity 0.000 description 6
- 230000036556 skin irritation Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 230000000699 topical effect Effects 0.000 description 6
- 206010002261 Androgen deficiency Diseases 0.000 description 5
- 108700012941 GNRH1 Proteins 0.000 description 5
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 239000003906 humectant Substances 0.000 description 5
- 230000002335 preservative effect Effects 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000004698 Polyethylene Substances 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 108010080146 androgen receptors Proteins 0.000 description 4
- 229940030486 androgens Drugs 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000004907 flux Effects 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 229920000573 polyethylene Polymers 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 229940124272 protein stabilizer Drugs 0.000 description 4
- 230000002459 sustained effect Effects 0.000 description 4
- 230000001839 systemic circulation Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- ALHUZKCOMYUFRB-UHFFFAOYSA-N 3-methylcyclopentadecan-1-one Chemical compound CC1CCCCCCCCCCCCC(=O)C1 ALHUZKCOMYUFRB-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010015150 Erythema Diseases 0.000 description 3
- 102000009151 Luteinizing Hormone Human genes 0.000 description 3
- 108010073521 Luteinizing Hormone Proteins 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000004809 Teflon Substances 0.000 description 3
- 229920006362 Teflon® Polymers 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000853 adhesive Substances 0.000 description 3
- 230000001070 adhesive effect Effects 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 229940059312 androderm Drugs 0.000 description 3
- 229940062331 androgel Drugs 0.000 description 3
- 238000013329 compounding Methods 0.000 description 3
- 239000006184 cosolvent Substances 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 231100000321 erythema Toxicity 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 230000002262 irrigation Effects 0.000 description 3
- 238000003973 irrigation Methods 0.000 description 3
- 229940040129 luteinizing hormone Drugs 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 238000010606 normalization Methods 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 230000037317 transdermal delivery Effects 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 2
- 102100032187 Androgen receptor Human genes 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- ZKVZSBSZTMPBQR-UHFFFAOYSA-N Civetone Natural products O=C1CCCCCCCC=CCCCCCCC1 ZKVZSBSZTMPBQR-UHFFFAOYSA-N 0.000 description 2
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 2
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 2
- 102000006771 Gonadotropins Human genes 0.000 description 2
- 108010086677 Gonadotropins Proteins 0.000 description 2
- 206010062767 Hypophysitis Diseases 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 102000001307 androgen receptors Human genes 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000037182 bone density Effects 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- ZKVZSBSZTMPBQR-UPHRSURJSA-N civetone Chemical compound O=C1CCCCCCC\C=C/CCCCCCC1 ZKVZSBSZTMPBQR-UPHRSURJSA-N 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 229940028334 follicle stimulating hormone Drugs 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 239000002622 gonadotropin Substances 0.000 description 2
- 230000036449 good health Effects 0.000 description 2
- 201000001881 impotence Diseases 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000001788 irregular Effects 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- UQDUPQYQJKYHQI-UHFFFAOYSA-N methyl laurate Chemical compound CCCCCCCCCCCC(=O)OC UQDUPQYQJKYHQI-UHFFFAOYSA-N 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000003961 penetration enhancing agent Substances 0.000 description 2
- 210000003635 pituitary gland Anatomy 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 230000035946 sexual desire Effects 0.000 description 2
- 230000036299 sexual function Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- VOCBWIIFXDYGNZ-IXKNJLPQSA-N testosterone enanthate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCCCC)[C@@]1(C)CC2 VOCBWIIFXDYGNZ-IXKNJLPQSA-N 0.000 description 2
- 229960003484 testosterone enanthate Drugs 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Natural products CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 229960000281 trometamol Drugs 0.000 description 2
- 210000000689 upper leg Anatomy 0.000 description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 1
- DBPWSSGDRRHUNT-CEGNMAFCSA-N 17α-hydroxyprogesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DBPWSSGDRRHUNT-CEGNMAFCSA-N 0.000 description 1
- 229940058020 2-amino-2-methyl-1-propanol Drugs 0.000 description 1
- QGXBDMJGAMFCBF-HLUDHZFRSA-N 5α-Androsterone Chemical compound C1[C@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC[C@H]21 QGXBDMJGAMFCBF-HLUDHZFRSA-N 0.000 description 1
- 229920002126 Acrylic acid copolymer Polymers 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010003041 Application site erythema Diseases 0.000 description 1
- 206010003046 Application site irritation Diseases 0.000 description 1
- 206010003053 Application site pruritus Diseases 0.000 description 1
- 206010003054 Application site rash Diseases 0.000 description 1
- 206010003055 Application site reaction Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 0 CC(**C*(C)=C)=NC Chemical compound CC(**C*(C)=C)=NC 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 206010012374 Depressed mood Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- QGXBDMJGAMFCBF-UHFFFAOYSA-N Etiocholanolone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC21 QGXBDMJGAMFCBF-UHFFFAOYSA-N 0.000 description 1
- 206010057671 Female sexual dysfunction Diseases 0.000 description 1
- 102000002265 Human Growth Hormone Human genes 0.000 description 1
- 108010000521 Human Growth Hormone Proteins 0.000 description 1
- 239000000854 Human Growth Hormone Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 206010058359 Hypogonadism Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000422980 Marietta Species 0.000 description 1
- 206010028289 Muscle atrophy Diseases 0.000 description 1
- ALHUZKCOMYUFRB-OAHLLOKOSA-N Muscone Chemical compound C[C@@H]1CCCCCCCCCCCCC(=O)C1 ALHUZKCOMYUFRB-OAHLLOKOSA-N 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- ORNBQBCIOKFOEO-YQUGOWONSA-N Pregnenolone Natural products O=C(C)[C@@H]1[C@@]2(C)[C@H]([C@H]3[C@@H]([C@]4(C)C(=CC3)C[C@@H](O)CC4)CC2)CC1 ORNBQBCIOKFOEO-YQUGOWONSA-N 0.000 description 1
- BNRNXUUZRGQAQC-UHFFFAOYSA-N Sildenafil Natural products CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 1
- 206010040914 Skin reaction Diseases 0.000 description 1
- 239000005035 Surlyn® Substances 0.000 description 1
- 206010043315 Testicular failure Diseases 0.000 description 1
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 206010047486 Virilism Diseases 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003522 acrylic cement Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000005250 alkyl acrylate group Chemical group 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000001195 anabolic effect Effects 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 229940061641 androsterone Drugs 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 210000000617 arm Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 description 1
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 150000003997 cyclic ketones Chemical class 0.000 description 1
- LXJDKGYSHYYKFJ-UHFFFAOYSA-N cyclohexadecanone Chemical compound O=C1CCCCCCCCCCCCCCC1 LXJDKGYSHYYKFJ-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000037336 dry skin Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000009547 dual-energy X-ray absorptiometry Methods 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 229920005648 ethylene methacrylic acid copolymer Polymers 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 description 1
- 210000002149 gonad Anatomy 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 239000002474 gonadorelin antagonist Substances 0.000 description 1
- 238000009578 growth hormone therapy Methods 0.000 description 1
- 102000036124 hormone binding proteins Human genes 0.000 description 1
- 108091011044 hormone binding proteins Proteins 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 230000000622 irritating effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 210000002332 leydig cell Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000011140 metalized polyester Substances 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- LOKPJYNMYCVCRM-UHFFFAOYSA-N omega-pentadecalactone Natural products O=C1CCCCCCCCCCCCCCCO1 LOKPJYNMYCVCRM-UHFFFAOYSA-N 0.000 description 1
- 238000009806 oophorectomy Methods 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920006267 polyester film Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- ORNBQBCIOKFOEO-QGVNFLHTSA-N pregnenolone Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 ORNBQBCIOKFOEO-QGVNFLHTSA-N 0.000 description 1
- 229960000249 pregnenolone Drugs 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000000518 rheometry Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000004999 sex organ Anatomy 0.000 description 1
- 230000009329 sexual behaviour Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 230000035938 sexual maturation Effects 0.000 description 1
- DEIYFTQMQPDXOT-UHFFFAOYSA-N sildenafil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 DEIYFTQMQPDXOT-UHFFFAOYSA-N 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 230000035483 skin reaction Effects 0.000 description 1
- 231100000430 skin reaction Toxicity 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 230000021595 spermatogenesis Effects 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- HPFVBGJFAYZEBE-ZLQWOROUSA-N testosterone cypionate Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(CCC(=O)C=C4CC3)C)CC[C@@]21C)C(=O)CCC1CCCC1 HPFVBGJFAYZEBE-ZLQWOROUSA-N 0.000 description 1
- 229960000921 testosterone cypionate Drugs 0.000 description 1
- 229960001712 testosterone propionate Drugs 0.000 description 1
- UDSFVOAUHKGBEK-CNQKSJKFSA-N testosterone undecanoate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCCCCCCCC)[C@@]1(C)CC2 UDSFVOAUHKGBEK-CNQKSJKFSA-N 0.000 description 1
- 229960000746 testosterone undecanoate Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- 229940094720 viagra Drugs 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/06—Anabolic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/26—Androgens
Definitions
- the present invention relates to a composition useful for the delivery of an androgen. More particularly, the present invention relates to a pharmaceutical composition comprising an androgen and an enhancer, that is, a material which is capable of increasing the rate of passage of an androgen through a body membrane.
- Androgens include, for example, 17 ⁇ -hydroxyandrost-4-en-3-one, commonly known as testosterone, and dihydrotestosterone (DHT), a metabolite of testosterone.
- Testosterone is a naturally-occurring androgen which is secreted in males and, to a much lesser extent, in females.
- testosterone and DHT are responsible for normal growth and development of the male sex organs and for maintenance of secondary sex characteristics.
- testosterone and DHT are believed to be important for normal growth, sexual desire, and sexual function.
- androgens promote retention of nitrogen, sodium, potassium, and phosphorus, and decrease the urinary excretion of calcium. Androgens have been reported to also increase protein anabolism, decrease protein catabolism, and stimulate the production of red blood cells.
- testosterone exists primarily bound to a protein, typically albumin or sex hormone binding protein. Unbound testosterone is referred to as “free testosterone” (FT).
- FT free testosterone
- total testosterone refers to the total amount of testosterone in the blood serum, that is, the combined amount of protein-bound testosterone and free testosterone.
- the typical half-life of testosterone in the blood serum ranges from 10 to 100 minutes.
- Androgens such as testosterone and DHT bind to androgen receptors on cells.
- the resulting androgen-receptor complex regulates gonadotropin secretion and spermatogenesis.
- the androgen-receptor complex is responsible also for external virilization and for most androgen actions during sexual maturation and adult life.
- DHT is an especially potent androgen because it binds with greater affinity to androgen receptors than testosterone does.
- Testosterone production is stimulated by luteinizing hormone (LH). It is believed that follicle stimulating hormone (FSH) stimulates testosterone production also. Testosterone concentrations in the blood serum are regulated in part by a negative-feedback pathway in which testosterone inhibits the formation and/or secretion of luteinizing hormone-releasing hormone (LHRH). LHRH stimulates the secretion of LH by the pituitary gland. Testosterone acts also by regulating the sensitivity of the pituitary gland to LHRH.
- LH luteinizing hormone
- FSH follicle stimulating hormone
- Male hypogonadism is a disorder in males resulting from or characterized by abnormally-decreased functional activity of the gonads. Male hypogonadism is manifested in the form of below-normal concentration of testosterone in the blood serum.
- the U.S. Federal Food and Drug Administration estimates that about 4 to 5 million Americans suffer from male hypogonadism and that male hypogonadism affects about 5 in every 1,000 men. It is believed that male hypogonadism affects 1 out of every 5 men aged over 50.
- Primary male hypogonadism is caused by testicular failure. Secondary male hypogonadism is caused by idiopathic gonadotropin, LHRH deficiency, or pituitary-hypothalamic injury.
- Various other causes of male hypogonadism include, for example, decline in the number of Leydig cells in the testes due to old age, and primary organic causes.
- Symptoms associated with male hypogonadism include decreased sexual desire with or without impotence, depression, decreased libido, fatigue and loss of energy, erectile dysfunction, mood depression, osteoporosis, reduced lean body mass, decreased muscle mass, decreased bone density, and regression of secondary sex characteristics.
- Causes of androgen deficiency in females include aging, oophorectomy, and ovary failure.
- Symptoms associated with female androgen deficiency include female sexual dysfunction, lack of desire, and muscle wasting.
- Exogenous androgen may alternatively be delivered parenterally directly into the systemic circulation. Such delivery allows for androgen to enter the systemic circulation directly, avoiding the gastrointestinal tract and the liver. Androgen delivered parenterally, however, is absorbed rapidly from the injection vehicle into the blood serum thus making a sustained delivery of androgen difficult to achieve and resulting in a sudden increase in androgen concentrations in the blood serum followed by a gradual decline. The rate of androgen absorption can be retarded with the use of esterified forms of androgen. Esterified forms of androgen are more soluble than non-esterified forms of androgen in the lipidic vehicles typically used for parenteral delivery.
- transdermal delivery of androgen avoids many of the disadvantages of oral and parenteral delivery. Such delivery is relatively painless and allows androgen to enter systemic circulation without having to first pass through the gastrointestinal tract or the liver.
- transdermal delivery of androgen involves the use of a transdermal patch which is adhered to the surface of the skin of the patient and which contains a reservoir of androgen that is absorbed by the skin.
- patches cause irritation of the skin, are often painful to remove, and are dislodged easily.
- patches are indiscrete in that they are noticeable when not covered, are large and bulky, and may leave a discolored area of skin after removal.
- the compositions contained in such patches are also often irritating to the skin.
- Another method for transdermal delivery of androgen involves the application directly to the skin of an androgen-containing composition in the form of a gel.
- a gel is referred to herein as a "topical gel" to distinguish it from other compositions which are in a gel form and which are contained within an article that is applied to the skin, for example, a transdermal patch.
- the present invention relates to the provision of an improved androgen-containing composition which can be applied directly to the skin for sustained delivery of androgen to an individual in need thereof.
- compositions in the form of a topical gel applied directly to the skin, for example, to the back, shoulders, upper arms, abdomen, or thighs.
- topical gels overcomes the previously-mentioned negative effects of a patch as well as the previously-mentioned negative pharmacokinetic effects of oral and parenteral androgen administration.
- a topical gel is typically in contact with a larger area of the skin relative to that contacted by a patch and, since the skin serves as an appropriate reservoir for the androgen delivered, a consistent normalization of androgen delivery into the blood serum over an extended period of time is able to be achieved.
- an androgen gel to deliver androgen effectively is often dependent on whether an enhancer, that is, a material which is capable of increasing the rate of passage of androgen through the skin or other body membrane, is used and the type of enhancer used.
- an enhancer that is, a material which is capable of increasing the rate of passage of androgen through the skin or other body membrane.
- topical androgen gels include those described in U.S. Patent Nos. 5,968,919 to Samour et al. and 6,503,894 to Dudley et al .
- the '919 patent describes a topical testosterone gel comprising also a dioxolane or a dioxane compound which functions as an enhancer.
- the topical testosterone gel described in the '894 patent also contains an enhancer, namely, isopropyl myristate.
- Disadvantages associated with the aforementioned topical androgen gels include, for example, the inconsistency of the gels and the lack of emollient properties; their use leads to drying of the skin and skin irritation.
- the gel of the '894 patent is capable of delivering a relatively low amount of testosterone through the skin and the gel of the '919 patent contains an enhancer which tends to irritate the skin.
- a pharmaceutical composition comprising: (A) an androgen; (B) a cyclic enhancer of the type described in U.S. Patent No. 5,023,252 to Hsieh (assigned to the same assignee as that of the present invention); and (C) a thickening agent.
- a composition exists in the form of a gel and comprises an enhancer which is a cyclic ester or a cyclic ketone.
- Another aspect of the present invention is a unit dose formulation which is effective in supplying testosterone transdermally to the blood of a male patient such that, following a single application of the unit dose to the patient, the amount of circulating testosterone (AUC 0-24 ) in the blood serum of the patient achieved in the 24-hour period following the application is about 100 to about 35,000 ng.h/dL greater than the amount of circulating testosterone (AUC 0-24 ) in the blood serum of the patient that would have been achieved in the same 24-hour period had the dose not been administered, said unit dose comprising up to about 1% by weight testosterone, about 0.01 to about 25% by weight of a cyclic enhancer of the type described in U.S. Patent No. 5,023,252 , to Hsieh, and about 0.1 to about 10% by weight of thickening agent, said testosterone being present in said unit dose in an amount of about 1 to about 300 mg.
- Another aspect of the present invention is a unit dose formulation which is effective in supplying testosterone transdermally to the blood of a female patient such that, following a single application of the unit dose to the patient, the amount of circulating testosterone (AUC 0-24 ) in the blood serum of the patient achieved in the 24-hour period following the application is about 0.10 to about 11,700 ng.h/dL greater than the amount of circulating testosterone (AUC 0-24 ) in the blood serum of the patient that would have been achieved in the same 24-hour period had the dose not been administered, said unit dose comprising up to about 1% by weight testosterone, about 0.01 to about 25% by weight of a cyclic enhancer of the type described in U.S. Patent No. 5,023,252 to Hsieh, and about 0.1 to about 10% by weight of thickening agent, said testosterone being present in said unit dose in an amount of about 0.01 to about 100 mg.
- Another aspect of the present invention is a unit dose formulation which is effective in supplying dihydrotestosterone transdermally to the blood of a male patient such that, following a single application of the unit dose to the patient, the amount of circulating dihydrotestosterone (AUC 0-24 ) in the blood serum of the patient achieved in the 24-hour period following the application is about 11,625 to about 465,000 pg.h/mL greater than the amount of circulating dihydrotestosterone (AUC 0-24 ) in the blood serum of the patient that would have been achieved in the same 24-hour period had the dose not been administered, said unit dose comprising up to about 1 % by weight dihydrotestosterone, about 0.01 to about 25% by weight of a cyclic enhancer of the type described in U.S. Patent No. 5,023,252 to Hsieh , and about 0.1 to about 10% by weight of thickening agent, said dihydrotestosterone being present in said unit dose in an amount of about 5 to about 200 mg.
- Another aspect of the present invention is a unit dose formulation which is effective in supplying dihydrotestosterone transdermally to the blood of a female patient such that, following a single application of the unit dose to the patient, the average dihydrotestosterone concentration (AUC 0-24 ) in the blood serum of the patient achieved in the 24-hour period following the application is about 11.6 about 232,500 pg.h/mL greater than the average dihydrotestosterone concentration (AUC 0-24 ) in the blood serum of the patient that would have been achieved in the same 24-hour period had the dose not been administered, said unit dose comprising up to about 1 % by weight dihydrotestosterone, about 0.01 to about 25 % by weight of a cyclic enhancer of the type described in U.S. Patent No. 5,023,252 to Hsieh , and about 0.1 to about 10% by weight of thickening agent, said dihydrotestosterone being present in said unit dose in an amount of about 0.005 to about 100 mg.
- Yet another aspect of the present invention is the provision of a use for supplying an androgen to a patient comprising the step of delivering to said patient a composition comprising an androgen, a cyclic enhancer of the type described in U.S. Patent No. 5,023,252 to Hsieh , and a thickening agent.
- Yet another aspect of the present invention is the provision of a method for supplying testosterone to a patient comprising the step of applying, once daily, to the shoulder or upper arm of a patient, a unit dose formulation which is effective in supplying testosterone transdermally to the blood of a patient such that, following a single application of the unit dose to the patient, the amount of circulating testosterone (AUC 0-24 ) in the blood serum of the patient achieved in the 24-hour period following the application is about 100 to about 35,000 ng.h/dL greater than the amount of circulating testosterone (AUC 0-24 ) in the blood serum of the patient that would have been achieved in the same 24-hour period had the dose not been administered, said unit dose comprising up to about 1% by weight testosterone, about 0.01 to about 25% by weight of a cyclic enhancer of the type described in U.S. Patent No. 5,023,252 , and about 0.1 to about 10% by weight of thickening agent, said testosterone being present in said unit dose in an amount of about 1 to about 300 mg.
- Yet another aspect of the present invention is a method for making a composition useful for treating a condition in a patient comprising the step of mixing an androgen, a cyclic enhancer of the type described in U.S. Patent No. 5,023,252 to Hsieh , and a thickening agent.
- Figure 1 is a graph comparing the 48-hour total testosterone pharmacokinetic profile for a first group of hypogonadal men following treatment with a single 5.0 g dose of a composition of the present invention with the 48-hour total testosterone pharmacokinetic profile for a second group of hypogonadal men following treatment with the 48-hour total testosterone pharmacokinetic profile for a second group of hypogonadal men following treatment with a single 5.0 g dose of the composition described in Comparative Example C-1 below.
- Figure 2 is a graph comparing the mean change in body composition from baseline to Day 90 for patients treated daily using 5 g/day of a composition of the present invention, patients treated using 10 g/day of this composition, patients treated using 2 patches/day containing the composition described in Comparative Example C-2 below, and patients who applied 10 g/day of a placebo composition.
- Figure 3 is a graph comparing skin irritation scores at Days 30, 60, and 90 for patients treated daily using 5 g/day of a composition of the present invention, patients treated using 10 g/day of this composition, patients treated using 2 patches/day containing the composition described in Comparative Example C-2 below, and patients who applied 10 g/day of a placebo composition.
- composition of the present invention comprises an androgen.
- androgen refers to: testosterone; dihydrotestosterone (DHT); and precursors, salts, complexes, and analogs of testosterone and DHT.
- precursors of testosterone and DHT include, for example, DHEA, pregnenolone, progesterone, 17-OH-progesterone, and androsterone.
- Examples of analogs of testosterone and DHT include: testosterone esters, including straight and branched C 1-18 alkyl esters (herein referred to as "simple alkyl esters”), for example, testosterone enanthate, testosterone propionate, testosterone undecanoate, and testosterone heptylate, and cycloaliphatic esters, for example, testosterone cypionate, testosterone cyclopentyl alkyl ester, and testosterone cyclohexyl alkyl ester; and the analogous esters of DHT.
- testosterone esters including straight and branched C 1-18 alkyl esters (herein referred to as "simple alkyl esters"), for example, testosterone enanthate, testosterone propionate, testosterone undecanoate, and testosterone heptylate, and cycloaliphatic esters, for example, testosterone cypionate, testosterone cyclopentyl alkyl ester, and testosterone cyclohexyl alkyl ester; and the analogous esters
- Androgen is present in the composition in a pharmaceutically-effective concentration.
- the composition of the present invention comprises also an enhancer, that is, a compound capable of increasing the rate of passage of an androgen through a body membrane, for example, skin and mucous membranes.
- A is a group having the structure wherein X and Y are as defined above; m and n are integers having a value from 1 to 20 and the sum of m+n is not greater than 25; p is an integer having a value of 0 or 1; q is an integer having a value of 0 or 1; r is an integer having a value of 0 or 1; and each of R, R 1 , R 2 , R 3 , R 4 , R 5
- Enhancers of the above structural formula are referred to herein as “Hsieh enhancers” and are described, for example, in aforementioned U.S. Patent No. 5,023,252 .
- Such enhancers are lipophilic and are "membrane-compatible", meaning that they do not cause damage to the membrane on which the composition of the composition of the present invention is to be applied (hereafter “target membrane”).
- target membrane Such enhancers produce also a low level of irritability or no irritability to the target membrane and, in fact, serve as an emollient.
- Preferred Hsieh enhancers for use in the present invention are macrocyclic enhancers.
- the term "macrocyclic” is used herein to refer to cyclic compounds having at least 12 carbons in the ring.
- macrocyclic enhancers for use in the present invention include: (A) macrocyclic ketones, for example, 3-methylcyclopentadecanone (muscone), 9-cycloheptadecen-1-one (civetone), cyclohexadecanone, and cyclopentadecanone (normuscone); and (B) macrocyclic esters, for example, pentadecalactones such as oxacyclohexadecan-2-one (cyclopentadecanolide; ⁇ -pentadecalactone).
- Oxacyclohexadecan-2-one and cyclopentadecanone are especially preferred. It has been observed during human clinical testing that only 2 to 4% of patients experienced application site events (e.g., erythema) when a composition of the present invention comprising oxacyclohexadecan-2-one was applied to a target membrane.
- the enhancer is present in the composition in a concentration effective to enhance penetration through the membrane of the androgen to be delivered.
- Various considerations should be taken into account in determining the amount of enhancer to use. Such considerations include, for example, the amount of flux (rate of passage through the membrane) achieved and the stability and compatibility of the components in the formulations. For guideline purposes, it is believed most applications will involve the use of the enhancer in an amount of about 0.01 to about 25 wt.% of the composition, more likely in an amount of about 0.1 to about 15 wt.% of the composition, and most likely in an amount of about 0.5 to about 15 wt.% of the composition.
- the composition of the present invention comprises also a thickening agent for use in increasing the viscosity of the composition. Increased viscosity retards the flow of the composition, thus allowing for improved surface cling. Increased viscosity retards also the movement of particles dispersed in the composition, allowing for compounds dispersed therein to remain suspended therein for relatively long periods of time.
- a gel with a viscosity of about 500 to about 20,000 cps, more likely about 2,000 cps to about 6,000 cps, and most likely about 2,800 cps to about 4,600 cps (as measured under standard conditions of measurement).
- DHT DHT or its salts, complexes, or analogs
- a gel with a viscosity of about 1,000 cps to 9,000 cps, more likely about 2,000 cps to about 8,000 cps and most like about 3,000 cps to about 7,000 cps (as measured under standard conditions of measurement).
- any suitable thickening agent or mixture of thickening agents can be used in the practice of the present invention.
- Preferred thickening agents are characterized by at least one of the following properties: low level of irritability or no irritability to the target membrane; bioadhesiveness; and being listed in the National Formulary or the U.S. Pharmacopeia.
- Preferred sources of thickening agents are those which do not include also residual components which may be detrimental to the membrane, for example, benzene and toluene.
- preferred thickening agents are those that are synthetic and not obtained from natural sources, thus reducing the risk of unwanted impurities.
- preferred thickening agents for use in the present invention include those which produce a low level of irritability or no irritability to the target membrane.
- thickening agents include: cellulosic thickening agents, for example, cellulose, hydroxyethyl-cellulose, carboxymethylcellulose, and hydroxypropylmethyl-cellulose; and acrylic thickening agents.
- preferred acrylic thickeners are carbomers, for example, non-linear polymers of acrylic acid cross-linked with a polyalkenyl polyether.
- preferred carbomers which may be used in the present invention include carboxypolymethylene, carboxyvinyl polymer, and alkyl acrylates, for example, acrylic acid/alkyl methacrylate copolymer.
- acrylic acid/alkyl methacrylate copolymer (Pemulen TR-1 ® ) is not used as the primary thickening agent, it is preferred that such be present as a co-thickening agent. This is because acrylic acid/alkyl methacrylate copolymer provides the composition with a smoother feel as compared with compositions which do not use acrylic acid/alkyl methacrylate copolymer and serves also as an emollient.
- the thickening agent is present in the composition in a concentration effective to provide the desired viscosity to the composition.
- concentration effective to provide the desired viscosity to the composition it is believed most applications will involve the use of the thickening agent in an amount of about 0.1 to about 10 wt.% of the composition and more likely in an amount of about 1 to about 6 wt.% of the composition.
- the composition of the present invention may comprise also a carrier which is capable of solubilizing one of more of the ingredients comprising the composition of the present invention.
- a carrier which is capable of solubilizing one of more of the ingredients comprising the composition of the present invention.
- any suitable carrier or mixture of carriers which is a suitable vehicle for the composition of the present invention can be used in the practice thereof.
- Preferred carriers are characterized by at least one of the following properties: low irritability or no irritability to the target membrane; being listed in the National Formulary or the U.S. Pharmacopeia; capability to enhance penetration of the androgen across a membrane; and capability to perform an additional function in the composition, for example, function also as an emollient, a humectant, a plasticizer, a lubricating agent, and/or a protein stabilizer.
- Alcohols are preferred primary solvents for use in the present invention because they are capable of solvating the active compounds and the thickening agent and, in compositions in which carbomers are used as the thickening agent, serve to swell the thickening agent. It is believed that alcohols may serve also to enhance the penetration of an androgen across a membrane. Examples of preferred alcohols are, for example, ethanol and isopropanol since such are capable of rapid evaporation, thus ensuring adequate permeation of the androgen though the target membrane.
- Preferred co-solvents include glycerin, propylene glycol, polyethylene, polypropylene, and silicones.
- glycerin serves as a humectant, an emollient, a plasticizer which plasticizes the stratum corneum of the skin, and a permeation enhancer and propylene glycol serves as an emollient and a permeation enhancer.
- the carrier is present in the composition in a concentration effective to serve as a suitable vehicle for the compositions of the present invention.
- concentration effective to serve as a suitable vehicle for the compositions of the present invention it is believed that most applications will involve the use of the carrier in an amount of about 40 to about 98 wt.% of the composition and more likely in an amount of about 50 to about 98 wt.% of the composition.
- applications will involve the use of ethanol or isopropanol in an amount of at least about 40 wt.% of the composition and generally about 40 to about 80 wt.% of the composition, more likely in an amount of about 50 to about 75 wt.% of the composition, and most likely in an amount of about 60 to about 75 wt.% of the composition.
- a carrier may be designed in which a first fluid which is miscible with or solvates the compound of interest evaporates more readily than a second fluid, which is immiscible with or partially miscible with or does not solvate the compound of interest.
- the first fluid evaporates, the compound of interest is left in a supersaturated environment in which it is favorable for the compound to pass into a less saturated environment, in this case through the membrane.
- oxacyclohexadecan-2-one is miscible with ethanol, but only partially miscible with propylene glycol and immiscible with water.
- a carrier may include ethanol and propylene glycol and/or water.
- testosterone is soluble in ethanol but not soluble in water and partially soluble in propylene glycol.
- a carrier may include ethanol and water or ethanol and propylene glycol.
- water may be used to prevent "reverse-flux", or the flow of water from the membrane into the matrix of the composition.
- composition of the present invention may comprise also a crystallization inhibitor capable of inhibiting the crystallization of an androgen.
- a crystallization inhibitor capable of inhibiting the crystallization of an androgen.
- any suitable crystallization inhibitor or mixture of such inhibitors can be used in the practice of the present invention.
- Preferred crystallization inhibitors function by lowering the temperature at which an androgen crystallizes.
- An example of such a crystallization inhibitor is polyethylene glycol 1000.
- the crystallization inhibitor is present in the composition in a concentration effective to inhibit the crystallization of the androgen.
- concentration effective to inhibit the crystallization of the androgen For guideline purposes, it is believed that most applications which comprise a crystallization inhibitor will involve the use of the crystallization inhibitor in an amount of about 0.001 to about 5 wt.% of the composition, more likely about 0.01 to about 2 wt.% of the composition, and most likely about 0.1 to about 1 wt.% of the composition.
- the composition of the present invention may comprise also a preservative capable of preventing oxidation of the components of the composition, microbial growth, or contamination.
- a preservative capable of preventing oxidation of the components of the composition, microbial growth, or contamination.
- a preservative or mixture of preservatives may be used in the practice of the present invention.
- Preferred preservatives include: food additive anti-microbial agents, for example, quaternary ammonium salts, sorbic acid, acetic acid, and benzoic acid or salts thereof; and antioxidants, for example, Vitamin C, Vitamin E, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT).
- antioxidants for example, Vitamin C, Vitamin E, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT).
- BHA butylated hydroxyanisole
- BHT butylated hydroxytoluene
- the preservative is present in the composition in a concentration effective to inhibit microbial growth, the oxidation of the components of the composition, or contamination of the composition.
- concentration effective to inhibit microbial growth, the oxidation of the components of the composition, or contamination of the composition For guideline purposes, it is believed that most applications which comprise a preservative will involve the use of the preservative in an amount of about 0.0001 to about 1.0 wt.% of the composition and more likely in an amount of about 0.005 to about 0.1 wt.% of the composition.
- a neutralizing agent may be included in the composition.
- any suitable neutralizing agent or mixture of neutralizing agents can be used in the practice of the present invention.
- Preferred neutralizing agents are characterized by at least one of the following properties: a pKa greater than about 9, with a pKa greater than about 9.5 being particularly preferred; and being compendial and approved for use by governmental agencies in pharmaceutical formulations.
- neutralizing agents which exhibit both of the above properties include triethanolamine, tromethamine, tris amino, triethylamine, 2-amino-2-methyl-1-propanol, sodium hydroxide, ammonium hydroxide, and potassium hydroxide.
- the choice of neutralizing agent for use in the present application should take into account the thickening agent used.
- the choice of neutralizing agent should take into account the primary solvent for the composition and the concentration of the primary solvent in the composition. If an inappropriate neutralizing agent is used, the thickening agent may precipitate out of solution.
- Noveon publication TRS-237 provides a chart showing examples of appropriate neutralizing agents for compositions with certain concentrations of alcoholic solvent.
- the neutralizing agent is present in the composition in a concentration effective to provide the desired viscosity to the composition.
- concentration effective to provide the desired viscosity to the composition it is believed that most applications which comprise a neutralizing agent will involve the use of the neutralizing agent in amount which will be sufficient to bring the pH of the composition to between about 3 and about 9, more likely between about 4 and about 8.
- composition of the present invention may include also additional optional ingredients which are art-recognized and in art-recognized quantities.
- materials may be added to modify the rheology, feel, slip, stability, humectancy, fragrance and other desirable physical properties that a practitioner may deem desirable.
- buffers may be added to maintain the composition at a certain pH.
- composition of the present invention may exist in various forms, for example, a gel, a cream, a lotion, an ointment, or a thickened solution.
- the composition preferably exists in the form of a gel.
- the composition exists in the form of a homogeneous gel which is capable of remaining homogeneous over the pharmaceutical lifetime thereof.
- the composition of the present invention preferably exhibits good yield value. Yield value measures the resistance of a composition to break down upon stress (e.g., when being rubbed onto skin).
- the composition should preferably also be capable of allowing for a consistent normalization of androgen delivery into the blood serum over an extended period of time. Additional preferred properties of the composition include emolliency (the producing of a low level of irritability or no irritability to a target membrane), lubricity, and ability to avoid pilling.
- composition of the present invention when used to deliver testosterone to a male patient, may be delivered in the form of a unit dose formulation which contains testosterone in an amount such that, following a single application of the unit dose to the patient, the amount of circulating testosterone (AUC 0-24 ) in the blood serum of the patient achieved in the 24-hour period following the application is about 100 to about 35,000 ng.h/dL, preferably about 600 to about 23,500 ng.h/dL, and most preferably about 2,900 to about 11,700 ng.h/dL greater than the amount of circulating testosterone (AUC 0-24 ) in the blood serum of the patient that would have been achieved in the same 24-hour period had the dose not been administered.
- Such a unit dose for male patients will involve the use of about 1 to about 300 mg of testosterone, more likely an amount of about 5 to about 200 mg testosterone, and most likely in an amount of about 25 to about 100 mg testosterone.
- the unit dose contains up to about 1 wt.% testosterone.
- composition of the present invention when used to deliver testosterone to a female patient, may be delivered in the form of a unit dose formulation which contains testosterone in an amount such that, following a single application of the unit dose to the patient, the amount of circulating testosterone (AUC 0-24 ) in the blood serum of the patient achieved in the 24-hour period following the application is about 0.10 to about 11,700 ng.h/dL, preferably about 100 to about 8,800 ng.h/dL, and most preferably about 600 to about 6,000 ng.h/dL greater than the average testosterone concentration (AUC 0-24 ) in the blood serum of the patient that would have been achieved in the same 24-hour period had the dose not been administered.
- AUC 0-24 average testosterone concentration
- Such a unit dose for female patients will involve the use of about 0.01 to about 100 mg of testosterone, more likely an amount of about 1 to about 75 mg testosterone, and most likely in an amount of about 5 to about 50 mg testosterone.
- the unit dose contains up to about 1 wt.% testosterone.
- composition of the present invention when used to deliver DHT to a male patient, may be delivered in the form of a unit dose formulation which contains DHT in an amount such that, following a single application of the unit dose to the patient, the amount of circulating DHT (AUC 0-24 ) in the blood serum of the patient achieved in the 24-hour period following the application is about 11,625 to about 465,000 pg.h/mL, preferably about 23,250 to about 232,500 pg.h/mL, and most preferably about 46,500 to about 116,250 pg.h/mL greater than the amount of circulating DHT (AUC 0-24 ) in the blood serum of the patient that would have been achieved in the same 24-hour period had the dose not been administered.
- Such a unit dose for male patients will involve the use of about 5 to about 200 mg of DHT, more likely an amount of about 10 to about 100 mg DHT, and most likely in an amount of about 20 to about 50 mg DHT.
- the unit dose contains up to about 1 wt.% DHT.
- composition of the present invention when used to deliver DHT to a female patient, may be delivered in the form of a unit dose formulation which contains DHT in an amount such that, following a single application of the unit dose to the patient, the amount of circulating DHT (AUC 0-24 ) in the blood serum of the patient achieved in the 24-hour period following the application is about 11.6 to about 232,500 pg.h/mL, preferably about 116 to about 116,250 pg.h/mL, and most preferably about 2,325 to about 58,100 pg.h/mL greater than the amount of circulating DHT (AUC 0-24 ) in the blood serum of the patient that would have been achieved in the same 24-hour period had the dose not been administered.
- Such a unit dose for female patients will involve the use of about 0.005 to about 100 mg of DHT, more likely an amount of about 0.05 to about 50 mg DHT, and most likely in an amount of about 1 to about 25 mg DHT.
- the unit dose contains up to about 1 wt.% DHT.
- composition of the present invention in gel form may be contained in a tube, a sachet, or a metered pump.
- a tube or sachet may contain one unit dose of the composition.
- a metered pump may be capable of dispensing one metered dose of the composition.
- a condition in a patient related to below-normal androgen concentration in the blood serum of the patient may be treated by administering to the patient a composition of the present invention.
- the composition may be delivered topically. If the composition is in the form of a gel, the composition may be rubbed onto a membrane of the patient, for example, the skin, preferably intact, clean, and dry skin, of the shoulder or upper arm and or the upper torso, and maintained thereon for a period of time sufficient for delivery of androgen to the blood serum of the patient.
- a preferred once daily dosage amount of a 1% testosterone gel of the present invention contains about 0.1 to about 30 grams of the composition, more preferably about 0.5 to about 20 grams of the composition, and most preferably about 2.5 to about 10 grams of the composition.
- a preferred once daily dosage amount of a 1% DHT gel of the present invention for the treatment of male hypogonadism contains about 0.5 to about 20 grams of the composition, more preferably about 1 to about 10 grams of the composition, and most preferably about 2 to about 5 grams of the composition.
- a preferred once daily dosage amount of a 1% testosterone gel of the present invention contains about 0.001 to about 10 grams of the composition, more preferably about 0.1 to about 7.5 grams of the composition, and most preferably about 0.5 to about 5 grams of the composition.
- a preferred once daily dosage amount of a 1% DHT gel of the present invention for the treatment of female testosterone deficiency contains about 0.0005 to about 10 grams of the composition, more preferably about 0.005 to about 5 grams of the composition, and most preferably about 0.1 to about 2.5 grams of the composition.
- the desired clinical response has not been achieved or if the androgen concentration in the blood serum of the patient is determined and found to remain below the normal adult concentration thereof, the amount of the dose, the frequency of the dose, and/or the number of applications of the dose may be increased.
- the androgen concentration in the blood serum of the patient is determined and found to be above the normal adult concentration thereof, the amount of the dose, the frequency of the dose, and/or the number of applications of the dose may be decreased.
- one or more of such unit doses may be administered to a patient, depending upon the condition to be treated, the amount of androgen to be delivered, and the frequency of administration.
- the number of such unit doses may be increased or decreased as needed, depending upon, as stated above, whether a desired clinical effect has been achieved and the concentration of androgen in the blood serum of the patient treated.
- composition of the present invention may be formulated by the use of conventional means, for example, by mixing and stirring the ingredients. Conventional equipment may be used.
- One of the advantages of the present invention is the ability to formulate the composition without resorting to unusual means to achieve the desired result. Simple glassware or stainless steel mixing vessels may be used.
- the composition can be formulated typically at room temperature or slightly above and at atmospheric pressures.
- compositions of the present invention includes examples of compositions of the present invention and of comparative compositions.
- composition which can be used as a topical gel for the delivery of testosterone and which is illustrative of a composition of the present invention.
- concentrations of the ingredients comprising the composition are given in percent by weight relative to the total weight of the composition.
- a composition comprising the above ingredients was prepared in a lot size of 1000 grams. All ingredients were weighed accurately to two decimal points and then added to a vessel. Oxacyclohexadecan-2-one, ethanol, propylene glycol, and glycerin were weighed in a bottle beaker. All compounding steps took place at approximately 22 °C. In between each step of addition and during stirring, a teflon stopper was placed on top of the vessel to prevent evaporation.
- composition which can be used as a topical gel for the delivery of dihydrotestosterone (DHT) and which is illustrative of a composition of the present invention.
- DHT dihydrotestosterone
- concentrations of the ingredients comprising the composition are given in percent by weight relative to the total weight of the composition.
- Wt.% dihydrotestosterone (Diosynth) 1.0 oxacyclohexadecan-2-one - enhancer 1.0 propylene glycol, USP - co-enhancer 5.0 carboxypolymethylene (BFGoodrich; sold as Carbopol 980 ® ) - thickening agent 1.0 acrylic acid/alkyl methacrylate copolymer (BFGoodrich; sold as Pemulen-TR1)- thickening agent 0.5 ethanol, 200 proof, USP - solvent 74.0 glycerin, USP - co-solvent, emollient, humectant, and protein stabilizer 1.0 polyethylene glycol 400, NF - crystallization inhibitor 0.25 tris amino crystal- neutralizing agent 0.08 water, sterile, for irrigation, USP 16.17
- a composition comprising the above ingredients was prepared in a lot size of 400 grams. All ingredients were weighed accurately to two decimal points and then added to a vessel. Oxacyclohexadecan-2-one, ethanol, propylene glycol, and glycerin were weighed in a bottle beaker. All compounding steps took place at ambient temperature In between each step of addition and during stirring, a teflon stopper was placed on top of the vessel to prevent evaporation.
- composition which can be used as a topical gel for the delivery of dihydrotestosterone (DHT) and which is illustrative of a composition of the present invention.
- DHT dihydrotestosterone
- concentrations of the ingredients comprising the composition are given in percent by weight relative to the total weight of the composition.
- This composition is similar to that described in Example 2 except that slightly less ethanol and slightly greater amounts of glycerin, polyethylene glycol 400, and water were used.
- a composition comprising the above ingredients was prepared in a lot size of 400 grams. All ingredients were weighed accurately to two decimal points and then added to a vessel. Oxacyclohexadecan-2-one, ethanol, propylene glycol, and glycerin were weighed in a bottle beaker. All compounding steps took place at ambient temperature In between each step of addition and during stirring, a teflon stopper was placed on top of the vessel to prevent evaporation.
- composition of AndroGel ® a topical 1 % testosterone gel: testosterone USP (testosterone comprises 1 wt. % of this composition), isopropyl myristate, carboxyvinyl polymer, sodium hydroxide, purified water, and ethanol (ethanol comprises 67.0 wt. % of this composition).
- the formulation of the No. 1 composition is as described in Example 1 with the exception that tromethamine, and not tris amino, was used as the neutralizing agent. Since large scale production was used to produce the No. 1 composition, various process and equipment changes were made as appropriate. Such appropriate changes are known to those of skill in the art and include changes in order of ingredient additions and mixing times. In addition, during the manufacturing process an overage of ethanol was added for the purpose of compensating for the evaporation thereof which occurs when larger equipment is used.
- the present study was conducted as a randomized, open-label, two-way complete crossover study.
- the patients each received a single 5 g dose of the composition of the No. 1 composition and a single 5 g dose of the C-1 composition seven days apart at different body sites (right/left shoulder).
- the composition was applied by the patient, using his hands, to intact, clean, and dry shoulder skin and rubbed until dry.
- Each dose contained 50 mg testosterone.
- Approximately 10 mL of whole blood samples were collected prior to dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 15, 18, 24, and 48 hours after dosing.
- the patients were housed and supervised during each dosing period from approximately 12 hours prior to dosing until after the 24-hour blood collection was completed.
- the 48-hour blood collection was collected the following day.
- Serum from the collected blood samples were separated by centrifugation of the blood samples at 1500 x g for 10 minutes at 18 °C. The resulting sera were transferred into plastic tubes and immediately frozen and stored at -20 °C ( ⁇ 3 °C) until assayed.
- the assay for total testosterone (T) was performed using the Coat-a Count ® Total Testosterone Assay Kit produced by Diagnostics Products Corporation.
- the assay for free testosterone (FT) was performed using the Coat-a-Count ® Free Testosterone Assay Kit produced by Diagnostics Products Corporation.
- the assay for dihydrotestosterone (DHT) was performed using the Active TM Dihydrotestosterone Assay Kit produced by Diagnostics Systems Laboratories. All assays were performed by ICON Laboratories, New York, USA.
- Serum concentrations of T, FT, and DHT were measured and the maximum concentrations thereof achieved over the 48-hour period (C max ) were determined.
- a serum concentration (not baseline-adjusted) vs. time curve was plotted for T, FT, and DHT (Figure 1 shows the curve for T).
- the area under the serum concentration vs. time curve from 0 to 24 hours as determined using the linear trapezoidal rule (AUC 0-24 ) was measured for T, FT, and DHT.
- the baseline-adjusted results are summarized in Tables 1 to 3 below.
- Table 1 Baseline Adjusted Total Testosterone - Mean (Standard Deviation) C max and AUC 0-24 Composition C max (ng/dL) AUC 0-24 (ng.h/dL) No. 1 480 ( ⁇ 70.3) 5864.5 ( ⁇ 77.9) C-1 ' 368 ( ⁇ 60.9) 4499.1 ( ⁇ 77.9)
- Table 2 Baseline Adjusted Free Testosterone - Mean (Standard Deviation) C max and AUC 0-24 Composition C max (ng/dL) AUC 0-24 (ng.h/dL) No.
- the above values in Tables 1 to 3 were estimated using WinNonlin pharmacokinetic software.
- the C max and AUC 0-24 values above are baseline-adjusted, with baseline being the pre-dose concentration.
- the adjustment for C max was made by subtracting the pre-dose concentration from the measured concentration. Several negative values were generated. These values were imputed with zero unless observed at the last sampling time point, in which case they were ignored for pharmacokinetic purposes.
- the adjustment for AUC 0-24 was made by subtracting the pre-dose concentration of testosterone in the blood serum of the patient from the measured concentration thereof at each sampling time over the 24-hour period (it is assumed that, in hypogonadal patients, the concentration of testosterone over the 24-hour period does not vary greatly).
- the mean baseline-adjusted C max following administration of the No. 1 composition was approximately 30% greater than the mean baseline-adjusted C max following administration of the C-1 composition.
- the mean baseline-adjusted C max following administration of the No. 1 composition was approximately 38% greater than the mean baseline-adjusted C max following administration of the C-1 composition.
- the median baseline-adjusted C max following administration of the No. 1 composition was approximately 2.5% greater than the median baseline-adjusted C max following administration of the C-1 composition.
- the mean AUC 0-24 following administration of the No. 1 composition was approximately 30% greater than the mean AUC 0.24 following administration of the C-1 composition.
- the mean AUC 0-24 following administration of the No. 1 composition was approximately 45% greater than the mean AUC 0-24 following administration of the C-1 composition.
- the mean AUC 0-24 following administration of the No. 1 composition was approximately 20% greater than the mean AUC 0-24 following administration of the C-1 composition.
- T normal male adult total testosterone
- composition which is used in the Androderm ® patch a transdermal patch used for delivering testosterone: testosterone USP; alcohol USP; glycerine USP; glycerol monooleate; methyl laurate; purified water USP; and acrylic acid copolymer.
- the Androderm ® patch has six components. Proceeding from the exterior toward the surface attached to the skin, the system is composed of: (A) a layer of metallized polyester/Surlyn ® (an ethylene-methacrylic acid copolymer/ethylene vinyl acetate backing film with alcohol resistant ink); (B) a reservoir containing the above composition; (C) a permeable polyethylene microporous membrane; and (D) a peripheral layer of acrylic adhesive surrounding the central active drug delivery area of the system. Prior to opening of the system and application to the skin, the central delivery surface of the system was sealed with a peelable laminate disc composed of a five-layer laminate containing polyester, polyesterurethane adhesive, aluminum foil, polyesterurethane adhesive, and polyethylene. The disc was attached to and removed with a release liner, a silicone-coated polyester film, which was removed before the system was used.
- Example 1 the “No. 1 composition”
- Example C-2 the “C-2 composition”
- All study drug treatments were applied in the morning and repeat applications occurred at the same time of day for the duration of the study.
- Each of the patients in the No. 1 groups and the placebo group applied the contents of two tubes a day with the contents of one tube applied to the skin of one shoulder and the contents of the other tube applied to the skin of the other shoulder.
- Patients allocated to receive the C-2 composition-containing patches applied two adhesive patches daily.
- Application sites included intact and clean skin of the back, abdomen, upper arms, and thighs. Patches were to be worn for 24 hours and then replaced each morning at approximately the same time.
- T total testosterone
- FT free testosterone
- DHT dihydrotestosterone
- the assay for T was performed using the Coat-a-Count ® Total Testosterone Assay Kit produced by Diagnostics Products Corporation.
- the assay for FT was performed using the Coat-a-Count ® Free Testosterone Assay Kit produced by Diagnostics Products Corporation.
- the assay for DHT was performed using the Active TM Dihydrotestosterone Assay Kit produced by Diagnostics Systems Laboratories.
- Table 5 shows total testosterone (T) concentrations for the above groups measured prior to treatment (baseline) and at Days 30 and 90.
- Table 6 below shows serum dihydrotestosterone concentrations for the above groups measured prior to treatment (baseline) and at Days 30 and 90.
- Table 6 Dihydrotestosterone Pharmacokinetics Dihydrotestosterone (mmol/L): Mean Days 30 and 90 No.
- TBM Total body mass
- LBM lean body mass
- FM fat mass
- %F percentage fat
- the incidence of treatment-related adverse events was 29.1 %, 36.9 %, 62.7 %, and 40.4 % in the 5 g/day No. 1 group, 10 g/day No. 1 group, C-2 group, and placebo group, respectively. While treatment in the No. 1 groups and the placebo group was relatively well tolerated over the 90-day study period, the C-2 group patients experienced a substantially higher rate of adverse events. Those most commonly seen were application-site erythema, application-site rash, application-site pruritus, application-site reactions, and application-site irritation.
- Figure 3 provides a graphic illustration of the frequency distribution of patients having positive skin irritation scores.
- the scoring system was based on a five-point categorical series from 0 (no erythema) through 4 (intense erythema with edema and blistering/erosion).
- events occurred predominately in the C-2 group and only a few mild reactions occurred in the No. 1 and placebo groups.
- the figure illustrates that the C-2-containing patches acted as an irritant in some patients who experienced classic signs of contact dermatitis and that the No. 1 group did not experience any more skin irritation than the placebo group.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Reproductive Health (AREA)
- Diabetes (AREA)
- Physical Education & Sports Medicine (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Gynecology & Obstetrics (AREA)
- Hematology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Obesity (AREA)
- Rheumatology (AREA)
- Pregnancy & Childbirth (AREA)
- Neurology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Steroid Compounds (AREA)
Claims (23)
- Eine pharmazeutische Zusammensetzung, umfassend:(A) 0,01 Gewichtsprozent bis 15 Gewichtsprozent eines Androgens, das aus der Gruppe ausgewählt ist, die aus Testosteron, Vorstufen von Testosteron, Salzen von Testosteron, Komplexen von Testosteron, Analoga von Testosteron, Derivaten von Testosteron, Dihydrotestosteron, Vorstufen von Dihydrotestosteron, Kongeneren von Dihydrotestesteron, Salzen von Dihydrotestosteron, Komplexen von Dihydrotestosteron, Analoga von Dihydrotestosteron und Derivaten von Dihydrotestosteron besteht;(B) 0,01 Gewichtsprozent bis 25 Gewichtsprozent eines Hsieh-Verstärkers der eine Verbindung mit der folgenden Strukturformel ist:(C) 0,1 Gewichtsprozent bis 10 Gewichtsprozent eines Verdickungsmittels
- Eine pharmazeutische Zusammensetzung gemäß Anspruch 1, umfassend:(A) das Androgen in einem Anteil von 0,01 bis 15 Gewichtsprozent, wobei das Androgen aus Testosteron und Dihydrotestosteron ausgewählt ist;(B) den Hsieh-Verstärker in einem Anteil von 0,01 bis 25 Gewichtsprozent vorliegt, wobei der Hsieh-Verstärker aus macrocyclischen Verstärkern ausgewählt ist;(C) das Verdickungsmittel in einem Anteil von 0,1 bis 10 Gewichtsprozent, wobei das Verdickungsmittel aus acrylischen Verdickungsmitteln und zelluloseartigen Verdickungsmitteln ausgewählt ist, und einen geringen Grad an irritation oder keine irritation an der Zielmembran bewirkt, wobei das Verdickungsmittel bioadhesive Eigenschaften aufweist; und(D) optional wenigstens eine zusätzliche Komponente, ausgewählt aus Neutralisationsmitteln,Trägermitteln wie Ethanol und Wasser, einschließlich einer Kombination aus Trägermitteln so dass das Androgen und der Verstärker in einem Trägermittel besser mischbar und in einem anderen weniger oder nicht mischbar sind; und
Kristallisationshemmer,
wobei die Zusammensetzung einen geringen Grad an irritation oder keine irritation an der Zielmembran hewirkt. - Eine pharmazeutische Zusammensetzung gemäß Anspruch 1 oder 2, die als eine Einheitsdosisformulierung formuliert ist, die dahingehend wirksam ist, Testosteron transdermal an das Blut eines weiblichen Patienten zu liefern, so dass nach einer einzelnen Anwendung der Einheitsdosis an dem Patienten die Menge des zirkulierenden Testosterons (AUC0-24) In dem Blutserum des Patienten, die in dem Zeitraum von 24 Stunden nach der Anwendung erreicht wird, um 0,10 bis 11700 ng·h/dl größer als die Menge des zirkulierenden Testosterons (AUC0-24) in dem Blutserum des Patienten ist die In dem gleichen Zeitraum von 24 Stundenlerreicht worden wäre, wenn man die Dosis nicht verabreicht hätte, wobei die Einheitsdosis das Folgende umfasst
0,01 Gewichtsprozent bis 10 Gewichtsprozent Testosteron,
0,01 Gewichtsprozent bis 25 Gewichtsprozent eines Hsieh-Vestäkers und
0,1 bis 10 Gewichtsprozent eines Verdickungsmittels,
wobei das Testosteron, das in der Einhebdosis vorhanden ist, in einer Menge von 0,01 bis 100 mg vorliegt. - Eine pharmazeutische Zusammensetzung gemäß Anspruch 1 oder 2, die als eine Einheitsdosisformulierung formuliert ist; die dahingehend wirksam ist, Dihydrotestosteron transdermal an das Blut eines weiblichen Patienten zu liefern so dass nach einer einzelnen Anwendung der Einheitsdosis an dem Patienten die durchschnittliche Konzentration von Dihydrotestosteron (AUC0-24) in dem Blutserum des Patienten, die in dem Zeitraum von 24 Stunden nach der Anwendung erreicht wird, um 11,6 bis 232500 pg·h/ml höher als die durchschnittliche Konzentration von Dihydrotestosteron (AUC0-24) in dem Blutserum des Patienten ist, die in dem gleichen Zeitraum von 24 Stunden erreicht worden wäre, wenn man die Dosis nicht verabreicht hatte, wobei die Einheitsdosis das Folgende umfasst:
0,01 Gewichtsprozent bis 10 Gewichtsprozent Dihydrotestosteron
0,01 Gewichtsprozent bis 25 Gewichtsprozent eines Hsieh-Verstärkers und
0,1 bis 10 Gewichtsprozent eines Verdickungsmittels,
wobei das Dihydrotestosteron, das in der Einheitsdosis vorhanden ist, in einer Menge von 0,005 bis 100 mg vorliegt. - Eine pharmazeutische Zusammensetzung gemäß Anspruch 1 oder 2, die 0,01 bis 10 Gewichtsprozent des Androgens umfasst.
- Eine pharmazeutische Zusammensetzung gemäß Anspruch 1 oder 2, die 0,1 bis 5 Gewichtsprozent des Androgens umfasst.
- Eine pharmazeutische Zusammensetzung gemäß Anspruch 1 oder 2 in der Form eines topischen Gels.
- Eine pharmazeutische Zusammensetzung gemäß Anspruch 1, umfassend:(A) 0,01 bis 15 Gewichtsprozent des Androgens,(B) 0,5 bis 15 Gewichtsprozent des Hsleh-Verstärkers und(C) 1 bis 6 Gewichtsprozent des Verdickungsmittels.
- Eine pharmazeutische Zusammensetzung gemäß Anspruch 8, wobei die Zusammensetzung in der Form eines homogenen topischen Gels vorliegt, die einen pH-Wert von 3 bis 9 aufweist, wobei
das Androgen Testosteron ist,
der Verstärker Oxacyclohexadecan-2-on ist,
das Verdickungsmittel Carboxypolymethylen und Acrylsäure/Methacrylat-Copolymer umfasst und
wobei die Zusammensetzung zusätzlich 40 bis 98 Gewichtsprozent eines Trägermittels, das Ethanol und Wasser enthält, sowie 0,001 bis 5 Gewichtsprozent eines Kristallisationshemmers umfasst. - Eine pharmazeutische Zusammensetzung gemäß Anspruch 2, die eine Menge des Neutralisationsmittels enthält, die ausreicht, um einen pH-Wert der Zusammensetzung zwischen 3 und 9 zur Verfügung zu-stellen.
- Eine pharmazeutische Zusammensetzung gemäß Anspruch 2, die eine Menge des Neutralisationsmittels enthält, die ausreicht, um einen pH-Wert der Zusammensetzung zwischen 4 und 8 zur Verfügung zu stellen.
- Eine pharmazeutische Zusammensetzung gemäß Anspruch 1, wobei das Androgen Testosteron ist, der Hsieh-Verstärker ein macrocyclischer Verstärker ist und das Verdickungsmittel ein acrylisches Verdickungsmittel ist.
- Eine pharmazeutische Zusammensetzung gemäß Anspruch 1, wobei das Androgen Testosteron ist, der Hsieh-Verstärker ein macrocyclisches Keton ist und das Verdickungsmittel ein Carbomer ist.
- Eine pharmazeutische Zusammensetzung gemäß Anspruch 3 oder 4, wobei der Hsieh-Verstärker ein macrocyclischer Verstärker ist und das Verdickungsmittel ein acrylisches Verdickungsmittel ist.
- Eine pharmazeutische Zusammensetzung gemäß Anspruch 13, wobei das Testosteron in einer Menge von 0.01 bis 10 Gewichtsprozent der Zusammertsetzung vorhanden ist, das macrocyclische Keton in einer Menge von 0,1 bis 15 Gewichtsprozent der Zusammensetzung vorhanden ist und das Verdickungsmittel in einer Menge von 1 bis ungefähr 6 Gewichtsprozent der Zusammensetzung vorhanden ist.
- Eine pharmazeutische Zusammensetzung gemäß Anspruch 15, wobei das Testosteron in einer Menge von 0,1 bis 5 Gewichtsprozent der Zusammensetzung vorhanden ist und das macrocyclische Keton in einer Menge von 0,5 bis 15 Gewichtsprozent der Zusammensetzung vorhanden ist
- Eine pharmazeutische Zusammensetzung gemäß Anspruch 14 oder 16, wobei der Verstärker Oxacyclohexadecan-2-on ist und das Verdickungsmittel Carboxypolymethylen und Acrylsäure/Alkylmethacrylat-Copolymer umfasst.
- Eine pharmazeutische Zusammensetzung gemäß Anspruch 17, die auch Ethanol als ein Lösungsmittel umfasst.
- Verwendung der pharmazeutischen Zusammensetzung gemäß Anspruch oder 2 zur Herstellung eines Medikaments, das zur Verabreichung von Androgen an einen Patienten nützlich ist.
- Verwendung gemäß Anspruch 19, wobei das Medikament ein Medikament zur topischen Verwendung ist.
- Verwendung gemäß Anspruch 20, wobei das Medikament zur transdermalen Verwendung vorgesehen ist.
- Verwendung der pharmazeutischen Zusammensetzung gemäß Anspruch 3 oder 4 zur Herstellung eines Medikaments als Einheitsdosis, das zur Verabreichung von Androgen an einen weiblichen Patienten durch das Auftragen des Medikaments auf die Schulter oder den oberen Arm eines Patienten nützlich ist, wobei das Medikament derart formuliert ist, dass wenn es auf die Schulter oder den oberen Arm des Patienten aufgetragen wird, die Verabreichung des Androgens durch das Einreiben des Inhalts des Einheitsdosismedikaments bis zur Trocknung erreicht werden kann.
- Ein Verfahren zur Herstellung einer pharmazeutischen Zusammensetzung von Anspruch 1, wobei das Verfahren den Schritt des Mlschens des Androgens, des Hsieh-Verstärkers und des Verdickungsmittels umfasst.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP06018822A EP1741433B1 (de) | 2002-04-19 | 2003-04-21 | Pharmazeutische Zusammensetzung enthaltend ein Androgen |
CY20071101504T CY1109005T1 (el) | 2002-04-19 | 2007-11-26 | Φαρμακευτικη συνθεση η οποια περιλαμβανει ενα ανδρογονο |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US37410302P | 2002-04-19 | 2002-04-19 | |
US374103P | 2002-04-19 | ||
PCT/US2003/012235 WO2003088974A1 (en) | 2002-04-19 | 2003-04-21 | Pharmaceutical composition |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP06018822A Division EP1741433B1 (de) | 2002-04-19 | 2003-04-21 | Pharmazeutische Zusammensetzung enthaltend ein Androgen |
Publications (3)
Publication Number | Publication Date |
---|---|
EP1425019A1 EP1425019A1 (de) | 2004-06-09 |
EP1425019A4 EP1425019A4 (de) | 2004-11-17 |
EP1425019B1 true EP1425019B1 (de) | 2007-08-29 |
Family
ID=29251138
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP03726373A Expired - Lifetime EP1425019B1 (de) | 2002-04-19 | 2003-04-21 | Pharmazeutische zusammensetzung enthaltend ein androgen |
EP06018822A Expired - Lifetime EP1741433B1 (de) | 2002-04-19 | 2003-04-21 | Pharmazeutische Zusammensetzung enthaltend ein Androgen |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP06018822A Expired - Lifetime EP1741433B1 (de) | 2002-04-19 | 2003-04-21 | Pharmazeutische Zusammensetzung enthaltend ein Androgen |
Country Status (30)
Country | Link |
---|---|
US (21) | US7320968B2 (de) |
EP (2) | EP1425019B1 (de) |
JP (1) | JP2005519985A (de) |
KR (2) | KR100952786B1 (de) |
CN (2) | CN1662243B (de) |
AR (2) | AR039644A1 (de) |
AT (1) | ATE371456T1 (de) |
AU (1) | AU2003228612B2 (de) |
BR (1) | BR0309390A (de) |
CA (1) | CA2470200C (de) |
CY (1) | CY1109005T1 (de) |
DE (1) | DE60315939T2 (de) |
DK (1) | DK1425019T3 (de) |
EA (1) | EA009839B1 (de) |
EG (1) | EG24882A (de) |
ES (2) | ES2292964T3 (de) |
HK (3) | HK1082682A1 (de) |
IL (1) | IL164547A (de) |
IS (2) | IS2667B (de) |
LT (1) | LT5235B (de) |
LV (1) | LV13303B (de) |
MX (1) | MXPA04010311A (de) |
MY (1) | MY139721A (de) |
NO (1) | NO335864B1 (de) |
NZ (1) | NZ535970A (de) |
PL (1) | PL213976B1 (de) |
SA (1) | SA03240158B1 (de) |
TW (1) | TWI362932B (de) |
WO (1) | WO2003088974A1 (de) |
ZA (1) | ZA200408422B (de) |
Families Citing this family (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040092494A9 (en) * | 2000-08-30 | 2004-05-13 | Dudley Robert E. | Method of increasing testosterone and related steroid concentrations in women |
US20030139384A1 (en) * | 2000-08-30 | 2003-07-24 | Dudley Robert E. | Method for treating erectile dysfunction and increasing libido in men |
US6503894B1 (en) | 2000-08-30 | 2003-01-07 | Unimed Pharmaceuticals, Inc. | Pharmaceutical composition and method for treating hypogonadism |
US20040002482A1 (en) * | 2000-08-30 | 2004-01-01 | Dudley Robert E. | Androgen pharmaceutical composition and method for treating depression |
US20040072810A1 (en) * | 2001-11-07 | 2004-04-15 | Besins International Belgique | Pharmaceutical composition in the form of a gel or a solution based on dihydrotestosterone, process for preparing it and uses thereof |
MY139721A (en) * | 2002-04-19 | 2009-10-30 | Cpex Pharmaceuticals Inc | Pharmaceutical composition |
US8883769B2 (en) * | 2003-06-18 | 2014-11-11 | White Mountain Pharma, Inc. | Methods for the treatment of fibromyalgia and chronic fatigue syndrome |
US20040259852A1 (en) * | 2003-06-18 | 2004-12-23 | White Hillary D. | Trandsdermal compositions and methods for treatment of fibromyalgia and chronic fatigue syndrome |
EP1634583A1 (de) | 2004-09-09 | 2006-03-15 | Laboratoires Besins International | Testosterongele enthaltend Propylenglykol als Resorptionsverstärker |
NZ553446A (en) * | 2004-09-09 | 2010-05-28 | Besins Int Lab | Testosterone gels comprising propylene glycol as penetration enhancer |
US20070088012A1 (en) * | 2005-04-08 | 2007-04-19 | Woun Seo | Method of treating or preventing type-2 diabetes |
ZA200803087B (en) | 2005-10-12 | 2009-11-25 | Unimed Pharmaceuticals Llc | Improved testosterone gel and method of use |
KR20110010763A (ko) * | 2008-05-09 | 2011-02-07 | 톨마 인코포레이티드 | 피부/점막 질환을 치료하기 위한 프로구아닐 |
KR20110020877A (ko) * | 2008-06-05 | 2011-03-03 | 씨펙스 파마슈티칼스, 인코포레이티드 | 인슐린의 경비형 제형 |
US20110097363A1 (en) * | 2009-10-22 | 2011-04-28 | Cpex Pharmaceuticals, Inc. | Therapeutically Effective Preparations of Insulin |
US9642862B2 (en) | 2010-11-18 | 2017-05-09 | White Mountain Pharma, Inc. | Methods for treating chronic or unresolvable pain and/or increasing the pain threshold in a subject and pharmaceutical compositions for use therein |
US20130045958A1 (en) | 2011-05-13 | 2013-02-21 | Trimel Pharmaceuticals Corporation | Intranasal 0.15% and 0.24% testosterone gel formulations and use thereof for treating anorgasmia or hypoactive sexual desire disorder |
US20130040923A1 (en) | 2011-05-13 | 2013-02-14 | Trimel Pharmaceuticals Corporation | Intranasal lower dosage strength testosterone gel formulations and use thereof for treating anorgasmia or hypoactive sexual desire disorder |
US9757388B2 (en) | 2011-05-13 | 2017-09-12 | Acerus Pharmaceuticals Srl | Intranasal methods of treating women for anorgasmia with 0.6% and 0.72% testosterone gels |
KR102088038B1 (ko) * | 2011-05-15 | 2020-03-13 | 에이세러스 바이오파마 인크. | 비내용 테스토스테론 겔의 조절된 방출, 경비성 투여를 위한 방법 및 미리-충전된 다회 용량 도포기 시스템 |
US10568905B2 (en) * | 2012-02-14 | 2020-02-25 | Metabolic Therapy Inc. | Pharmaceutical composition and method for treating retinal neurodegeneration |
JP6457383B2 (ja) | 2012-04-06 | 2019-01-23 | アンタレス・ファーマ・インコーポレーテッド | テストステロン組成物の針支援式ジェット注入投与 |
AU2013318229B2 (en) | 2012-09-20 | 2017-07-06 | Gkn Armstrong Wheels, Inc. | Lock ring spreader |
US11744838B2 (en) | 2013-03-15 | 2023-09-05 | Acerus Biopharma Inc. | Methods of treating hypogonadism with transnasal testosterone bio-adhesive gel formulations in male with allergic rhinitis, and methods for preventing an allergic rhinitis event |
US8785426B1 (en) | 2013-12-13 | 2014-07-22 | Upsher-Smith Laboratories, Inc. | Testosterone gel compositions and related methods |
US20170014417A1 (en) | 2015-07-14 | 2017-01-19 | Lipp Life Sciences Llc | Pharmaceutical administration system for the transdermal application of vardenafil |
WO2019089942A1 (en) * | 2017-11-02 | 2019-05-09 | Rick Coulon | Formulations for use in the transdermal delivery of proteasome inhibitors |
CN112666197B (zh) * | 2020-11-29 | 2022-11-04 | 山东大学 | 一种用于tbm的岩渣石英含量测试系统及方法 |
Family Cites Families (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4316893A (en) * | 1975-06-19 | 1982-02-23 | Nelson Research & Development Co. | Vehicle composition containing 1-substituted azacycloalkan-2-ones |
US4405616A (en) * | 1975-06-19 | 1983-09-20 | Nelson Research & Development Company | Penetration enhancers for transdermal drug delivery of systemic agents |
BE843140A (fr) * | 1975-06-19 | 1976-10-18 | Aazacycloalcan-2-ones 1-substituees et compositions pharmaceutiques contenant ces composes a titre d'excipients | |
US3989815A (en) * | 1975-06-19 | 1976-11-02 | Nelson Research & Development Company | Novel N-bis-azacyclopentan-2-onyl alkanes |
US3989816A (en) * | 1975-06-19 | 1976-11-02 | Nelson Research & Development Company | Vehicle composition containing 1-substituted azacycloheptan-2-ones |
US3991203A (en) * | 1975-06-19 | 1976-11-09 | Nelson Research & Development Company | Vehicle composition containing 1-substituted azacyclopentan-2-ones |
US4424210A (en) * | 1980-04-04 | 1984-01-03 | Nelson Research & Development Company | Vehicle composition containing 1-substituted azacycloalkan-2-ones |
US4423040A (en) * | 1980-04-04 | 1983-12-27 | Nelson Research & Development Company | Vehicle composition containing 1-substituted azacyclohexan-2-ones |
US4444762A (en) * | 1980-04-04 | 1984-04-24 | Nelson Research & Development Company | Vehicle composition containing 1-substituted azacyclopentan-2-ones |
US4415563A (en) * | 1980-04-04 | 1983-11-15 | Nelson Research & Development Company | Vehicle composition containing 1-substituted azacyclononan-2-ones |
US5023252A (en) * | 1985-12-04 | 1991-06-11 | Conrex Pharmaceutical Corporation | Transdermal and trans-membrane delivery of drugs |
US5731303A (en) | 1985-12-04 | 1998-03-24 | Conrex Pharmaceutical Corporation | Transdermal and trans-membrane delivery compositions |
US4992422A (en) * | 1986-01-31 | 1991-02-12 | Whitby Research, Inc. | Compositions comprising 1-substituted azacycloalkanes |
US5270346A (en) | 1986-01-31 | 1993-12-14 | Whitby Research, Inc. | Penetration enhancers for transdermal delivery of systemic agents |
US4801586A (en) | 1986-04-23 | 1989-01-31 | Nelson Research & Development Co. | Penetration enhancers for transdermal delivery of systemic agents |
US4879275A (en) | 1987-09-30 | 1989-11-07 | Nelson Research & Development Co. | Penetration enhancers for transdermal delivery of systemic agent |
US5019395A (en) * | 1988-03-08 | 1991-05-28 | Warner-Lambert Company | Compositions with enhanced penetration |
US5676968A (en) * | 1991-10-31 | 1997-10-14 | Schering Aktiengesellschaft | Transdermal therapeutic systems with crystallization inhibitors |
US6190691B1 (en) * | 1994-04-12 | 2001-02-20 | Adolor Corporation | Methods for treating inflammatory conditions |
GB9516268D0 (en) * | 1995-08-08 | 1995-10-11 | Danbiosyst Uk | Compositiion for enhanced uptake of polar drugs from the colon |
DE19619045C1 (de) * | 1996-05-02 | 1997-11-13 | Jenapharm Gmbh | Verwendung von Kombinationspräparaten zur Behandlung hypogonadaler Männer sowie Männern mit Hypophysenerkrankungen |
US5980898A (en) * | 1996-11-14 | 1999-11-09 | The United States Of America As Represented By The U.S. Army Medical Research & Material Command | Adjuvant for transcutaneous immunization |
US6019997A (en) * | 1997-01-09 | 2000-02-01 | Minnesota Mining And Manufacturing | Hydroalcoholic compositions for transdermal penetration of pharmaceutical agents |
DE19701949A1 (de) * | 1997-01-13 | 1998-07-16 | Jenapharm Gmbh | Transdermales therapeutisches System |
EP0988046B1 (de) * | 1997-01-30 | 2004-09-15 | Novartis AG | Ölfreie pharmazeutische zusammensetzung welche cyclosporin enthält |
DE29704393U1 (de) * | 1997-03-11 | 1997-07-17 | Aesculap Ag, 78532 Tuttlingen | Vorrichtung zur präoperativen Bestimmung der Positionsdaten von Endoprothesenteilen |
US5968919A (en) * | 1997-10-16 | 1999-10-19 | Macrochem Corporation | Hormone replacement therapy drug formulations for topical application to the skin |
IL136042A (en) * | 1997-11-10 | 2005-12-18 | Cellegy Pharma Inc | Alcohol-containing composition for topical application |
US6980952B1 (en) * | 1998-08-15 | 2005-12-27 | Texas Instruments Incorporated | Source normalization training for HMM modeling of speech |
EP1031564A1 (de) * | 1999-02-26 | 2000-08-30 | Klinge Pharma GmbH | Hemmer der Nicotinamidmonononukleotide-Bildung und deren Verwendung zur Krebstherapie |
FR2801507B1 (fr) * | 1999-11-30 | 2003-06-27 | Pf Medicament | Dispositif transdermique auto-adhesif comprenant un reservoir et une matrice contenant le meme principe actif, son procede de preparation et ses utilisations |
HUP0201450A3 (en) * | 1999-12-08 | 2003-02-28 | Pharmacia Corp Chicago | Solid-state form of celecoxib having enhanced bioavailability, pharmaceutical compositions containing it and their preparation |
US6495124B1 (en) | 2000-02-14 | 2002-12-17 | Macrochem Corporation | Antifungal nail lacquer and method using same |
US20040198706A1 (en) * | 2003-03-11 | 2004-10-07 | Carrara Dario Norberto R. | Methods and formulations for transdermal or transmucosal application of active agents |
US7198801B2 (en) * | 2000-08-03 | 2007-04-03 | Antares Pharma Ipl Ag | Formulations for transdermal or transmucosal application |
DE60143360D1 (de) * | 2000-08-03 | 2010-12-09 | Antares Pharma Ipl Ag | Zusammensetzung zur transdermalen und/oder transmukosalen Verabreichung von Wirkstoffen, die ausreichende therapeutische Spiegel garantiert |
US20040002482A1 (en) * | 2000-08-30 | 2004-01-01 | Dudley Robert E. | Androgen pharmaceutical composition and method for treating depression |
PL205279B1 (pl) | 2000-08-30 | 2010-03-31 | Besins International Lab | Zastosowanie żelu hydroalkoholowego zawierającego testosteron i zestaw do leczenia zaburzenia erekcji |
US6503894B1 (en) | 2000-08-30 | 2003-01-07 | Unimed Pharmaceuticals, Inc. | Pharmaceutical composition and method for treating hypogonadism |
US20030139384A1 (en) | 2000-08-30 | 2003-07-24 | Dudley Robert E. | Method for treating erectile dysfunction and increasing libido in men |
PL360992A1 (en) * | 2000-08-30 | 2004-09-20 | Unimed Pharmaceuticals,Inc. | Method of increasing testosterone and related steroid concentrations in women |
US20040092494A9 (en) * | 2000-08-30 | 2004-05-13 | Dudley Robert E. | Method of increasing testosterone and related steroid concentrations in women |
WO2002055020A2 (en) * | 2000-12-11 | 2002-07-18 | Testocreme Llc | Topical testosterone formulations and associated methods |
EP1347764B1 (de) * | 2000-12-22 | 2007-03-14 | Dr. August Wolff GmbH & Co. KG Arzneimittel | Gelzusammensetzung auf alkoholischer basis zur behandlung von hypogonadismus durch transskrotale applikation |
WO2002089849A1 (en) * | 2001-05-07 | 2002-11-14 | Corium International | Compositions and delivery systems for administration of a local anesthetic agent |
US20030027804A1 (en) * | 2001-06-27 | 2003-02-06 | Van Der Hoop Roland Gerritsen | Therapeutic combinations for the treatment of hormone deficiencies |
US7169107B2 (en) * | 2002-01-25 | 2007-01-30 | Karen Jersey-Willuhn | Conductivity reconstruction based on inverse finite element measurements in a tissue monitoring system |
WO2004091631A1 (en) | 2002-03-15 | 2004-10-28 | Unimed Pharmaceuticals, Inc. | Androgen pharmaceutical composition and method for treating depression |
MY139721A (en) * | 2002-04-19 | 2009-10-30 | Cpex Pharmaceuticals Inc | Pharmaceutical composition |
US20040259784A1 (en) * | 2003-06-18 | 2004-12-23 | White Hillary D. | Compositions and methods for treatment of muscle pain and muscle wasting |
-
2003
- 2003-04-18 MY MYPI20031462A patent/MY139721A/en unknown
- 2003-04-19 EG EG2003040351A patent/EG24882A/xx active
- 2003-04-21 WO PCT/US2003/012235 patent/WO2003088974A1/en active IP Right Grant
- 2003-04-21 EP EP03726373A patent/EP1425019B1/de not_active Expired - Lifetime
- 2003-04-21 AR ARP030101362A patent/AR039644A1/es not_active Application Discontinuation
- 2003-04-21 CA CA002470200A patent/CA2470200C/en not_active Expired - Fee Related
- 2003-04-21 DE DE60315939T patent/DE60315939T2/de not_active Expired - Lifetime
- 2003-04-21 CN CN038142368A patent/CN1662243B/zh not_active Expired - Fee Related
- 2003-04-21 AT AT03726373T patent/ATE371456T1/de active
- 2003-04-21 ES ES03726373T patent/ES2292964T3/es not_active Expired - Lifetime
- 2003-04-21 TW TW092109215A patent/TWI362932B/zh not_active IP Right Cessation
- 2003-04-21 KR KR1020047016828A patent/KR100952786B1/ko not_active IP Right Cessation
- 2003-04-21 EP EP06018822A patent/EP1741433B1/de not_active Expired - Lifetime
- 2003-04-21 DK DK03726373T patent/DK1425019T3/da active
- 2003-04-21 US US10/473,724 patent/US7320968B2/en active Active - Reinstated
- 2003-04-21 EA EA200401410A patent/EA009839B1/ru not_active IP Right Cessation
- 2003-04-21 ES ES06018822T patent/ES2399900T3/es not_active Expired - Lifetime
- 2003-04-21 CN CN201110259341.7A patent/CN102357098B/zh not_active Expired - Fee Related
- 2003-04-21 AU AU2003228612A patent/AU2003228612B2/en not_active Ceased
- 2003-04-21 NZ NZ535970A patent/NZ535970A/en not_active IP Right Cessation
- 2003-04-21 JP JP2003585726A patent/JP2005519985A/ja active Pending
- 2003-04-21 KR KR1020097013431A patent/KR100977896B1/ko not_active IP Right Cessation
- 2003-04-21 BR BR0309390-5A patent/BR0309390A/pt not_active IP Right Cessation
- 2003-04-21 PL PL372083A patent/PL213976B1/pl unknown
- 2003-04-21 MX MXPA04010311A patent/MXPA04010311A/es active IP Right Grant
- 2003-06-22 SA SA03240158A patent/SA03240158B1/ar unknown
-
2004
- 2004-10-13 IL IL164547A patent/IL164547A/en not_active IP Right Cessation
- 2004-10-18 ZA ZA200408422A patent/ZA200408422B/en unknown
- 2004-10-27 LV LVP-04-127A patent/LV13303B/en unknown
- 2004-11-17 IS IS7535A patent/IS2667B/is unknown
- 2004-11-18 NO NO20045019A patent/NO335864B1/no not_active IP Right Cessation
- 2004-11-18 LT LT2004101A patent/LT5235B/lt not_active IP Right Cessation
-
2006
- 2006-02-28 HK HK06102651.0A patent/HK1082682A1/xx not_active IP Right Cessation
-
2007
- 2007-05-25 HK HK07105491.6A patent/HK1098386A1/xx not_active IP Right Cessation
- 2007-10-30 US US11/928,467 patent/US7935690B2/en not_active Expired - Fee Related
- 2007-10-30 US US11/929,610 patent/US20080103120A1/en not_active Abandoned
- 2007-10-31 US US11/930,812 patent/US8063029B2/en not_active Expired - Fee Related
- 2007-10-31 US US11/931,809 patent/US8178518B2/en not_active Expired - Fee Related
- 2007-11-26 CY CY20071101504T patent/CY1109005T1/el unknown
-
2009
- 2009-01-20 US US12/356,513 patent/US7608605B2/en not_active Expired - Fee Related
- 2009-01-20 US US12/356,515 patent/US7608606B2/en not_active Expired - Fee Related
- 2009-01-21 US US12/356,943 patent/US7608607B2/en not_active Expired - Fee Related
- 2009-01-23 US US12/359,183 patent/US7608609B2/en not_active Expired - Fee Related
- 2009-01-23 US US12/359,162 patent/US7608608B2/en not_active Expired - Fee Related
- 2009-02-02 US US12/364,413 patent/US7608610B2/en not_active Expired - Fee Related
- 2009-03-19 US US12/407,418 patent/US20090192131A1/en not_active Abandoned
- 2009-03-19 US US12/407,460 patent/US20090192132A1/en not_active Abandoned
- 2009-09-30 US US12/570,847 patent/US20100081640A1/en not_active Abandoned
-
2010
- 2010-01-06 IS IS8870A patent/IS2946B/is unknown
-
2012
- 2012-04-11 US US13/444,637 patent/US20210308145A1/en not_active Abandoned
- 2012-08-03 US US13/566,633 patent/US20210308146A1/en not_active Abandoned
- 2012-08-08 AR ARP120102894A patent/AR087484A2/es unknown
- 2012-08-16 HK HK12108063.1A patent/HK1167332A1/xx not_active IP Right Cessation
- 2012-08-31 US US13/601,572 patent/US20130059828A1/en not_active Abandoned
-
2013
- 2013-06-19 US US13/921,879 patent/US20130281416A1/en not_active Abandoned
-
2014
- 2014-03-04 US US14/196,705 patent/US20140343025A1/en not_active Abandoned
-
2015
- 2015-04-07 US US14/680,197 patent/US20150283153A1/en not_active Abandoned
-
2016
- 2016-01-19 US US15/000,848 patent/US20160129016A1/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
None * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7935690B2 (en) | Pharmaceutical composition |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20040113 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL SE SK TR |
|
AX | Request for extension of the european patent |
Extension state: AL LT LV MK |
|
A4 | Supplementary search report drawn up and despatched |
Effective date: 20041006 |
|
17Q | First examination report despatched |
Effective date: 20050407 |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
RTI1 | Title (correction) |
Free format text: PHARMACEUTICAL COMPOSITION COMPRISING AN ANDROGEN |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE PATENT HAS BEEN GRANTED |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL SE SK TR |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D |
|
REF | Corresponds to: |
Ref document number: 60315939 Country of ref document: DE Date of ref document: 20071011 Kind code of ref document: P |
|
REG | Reference to a national code |
Ref country code: SE Ref legal event code: TRGR |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: NV Representative=s name: ISLER & PEDRAZZINI AG |
|
REG | Reference to a national code |
Ref country code: GR Ref legal event code: EP Ref document number: 20070403567 Country of ref document: GR |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: T3 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2292964 Country of ref document: ES Kind code of ref document: T3 |
|
ET | Fr: translation filed | ||
REG | Reference to a national code |
Ref country code: HU Ref legal event code: AG4A Ref document number: E002970 Country of ref document: HU |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
26N | No opposition filed |
Effective date: 20080530 |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: 732E |
|
REG | Reference to a national code |
Ref country code: EE Ref legal event code: GB1A Ref document number: E001767 Country of ref document: EE Owner name: CPEX PHARMACEUTICALS, INC., US |
|
NLS | Nl: assignments of ep-patents |
Owner name: CPEX PHARMACEUTICALS, INC. Effective date: 20090327 |
|
REG | Reference to a national code |
Ref country code: HU Ref legal event code: GB9C Owner name: CPEX PHARMACEUTICALS, INC., US Free format text: FORMER OWNER(S): BENTLEY PHARMACEUTICALS, INC., US Ref country code: HU Ref legal event code: FH1C Free format text: FORMER REPRESENTATIVE(S): FRANKNE DR. MACHYTKA DAISY, GOEDOELLE, KEKES, MESZAROS & SZABO SZABADALMI ES VEDJEGY IRODA, HU Representative=s name: GOEDOELLE, KEKES, MESZAROS & SZABO SZABADALMI , HU |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PUE Owner name: CPEX PHARMACEUTICALS, INC. Free format text: BENTLEY PHARMACEUTICALS, INC.#BENTLEY PARK, 2 HOLLAND WAY#EXETER, NH 03833 (US) -TRANSFER TO- CPEX PHARMACEUTICALS, INC.#2 HOLLAND WAY#EXETER, NH 03833 (US) |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: TP |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: PC2A |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: 732E Free format text: REGISTERED BETWEEN 20110505 AND 20110511 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: TP |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R082 Ref document number: 60315939 Country of ref document: DE Representative=s name: GRUENECKER, KINKELDEY, STOCKMAIR & SCHWANHAEUS, DE |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: PC2A Owner name: FCB I LLC Effective date: 20110801 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R082 Ref document number: 60315939 Country of ref document: DE Representative=s name: GRUENECKER, KINKELDEY, STOCKMAIR & SCHWANHAEUS, DE Effective date: 20110802 Ref country code: DE Ref legal event code: R081 Ref document number: 60315939 Country of ref document: DE Owner name: FCB I LLC, US Free format text: FORMER OWNER: CPEX PHARMACEUTICALS, INC. (N. D. GES. D. STAATES DELAWARE ), EXETER, US Effective date: 20110802 Ref country code: DE Ref legal event code: R081 Ref document number: 60315939 Country of ref document: DE Owner name: FCB I LLC, WILMINGTON, US Free format text: FORMER OWNER: CPEX PHARMACEUTICALS, INC. (N. D. GES. D. STAATES DELAWARE ), EXETER, N.H., US Effective date: 20110802 Ref country code: DE Ref legal event code: R082 Ref document number: 60315939 Country of ref document: DE Representative=s name: GRUENECKER PATENT- UND RECHTSANWAELTE PARTG MB, DE Effective date: 20110802 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: TR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20090611 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: TR Payment date: 20090508 Year of fee payment: 7 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 14 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NL Payment date: 20160526 Year of fee payment: 14 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 20160525 Year of fee payment: 14 Ref country code: ES Payment date: 20160527 Year of fee payment: 14 Ref country code: FI Payment date: 20160609 Year of fee payment: 14 Ref country code: DE Payment date: 20160601 Year of fee payment: 14 Ref country code: CH Payment date: 20160526 Year of fee payment: 14 Ref country code: MC Payment date: 20160609 Year of fee payment: 14 Ref country code: GR Payment date: 20160614 Year of fee payment: 14 Ref country code: CZ Payment date: 20160602 Year of fee payment: 14 Ref country code: LU Payment date: 20160610 Year of fee payment: 14 Ref country code: BG Payment date: 20160610 Year of fee payment: 14 Ref country code: IE Payment date: 20160609 Year of fee payment: 14 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 20160613 Year of fee payment: 14 Ref country code: SK Payment date: 20160606 Year of fee payment: 14 Ref country code: DK Payment date: 20160610 Year of fee payment: 14 Ref country code: EE Payment date: 20160628 Year of fee payment: 14 Ref country code: SE Payment date: 20160526 Year of fee payment: 14 Ref country code: FR Payment date: 20160613 Year of fee payment: 14 Ref country code: HU Payment date: 20160610 Year of fee payment: 14 Ref country code: AT Payment date: 20160609 Year of fee payment: 14 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: IT Payment date: 20160621 Year of fee payment: 14 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CY Payment date: 20160608 Year of fee payment: 14 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R119 Ref document number: 60315939 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: EE Ref legal event code: MM4A Ref document number: E001767 Country of ref document: EE Effective date: 20170430 |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: EBP Effective date: 20170430 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: MM Effective date: 20170501 |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MM01 Ref document number: 371456 Country of ref document: AT Kind code of ref document: T Effective date: 20170421 |
|
GBPC | Gb: european patent ceased through non-payment of renewal fee |
Effective date: 20170421 |
|
REG | Reference to a national code |
Ref country code: SK Ref legal event code: MM4A Ref document number: E 2720 Country of ref document: SK Effective date: 20170421 |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: MM4A |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: ST Effective date: 20171229 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MC Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170502 Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170502 Ref country code: SK Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170421 Ref country code: AT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170421 Ref country code: EE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170430 Ref country code: HU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170422 Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20171103 Ref country code: CZ Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170421 Ref country code: FI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170421 Ref country code: NL Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170501 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170422 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170430 Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170421 Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170421 Ref country code: CY Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170421 Ref country code: GR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20171103 Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170430 |
|
REG | Reference to a national code |
Ref country code: BE Ref legal event code: MM Effective date: 20170430 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170421 Ref country code: DK Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170430 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170421 Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170430 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FD2A Effective date: 20180628 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: ES Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170422 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BG Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20171105 |